Brand Names: U.S.

KlonoPIN

Pharmacologic Category

Anticonvulsant, Benzodiazepine

Benzodiazepine

Pharmacology

The exact mechanism is unknown, but believed to be related to its ability to enhance the activity of GABA; suppresses the spike-and-wave discharge in absence seizures by depressing nerve transmission in the motor cortex.

Off Label Uses

Bipolar disorder, manic or mixed episodes (adults)

Data from a meta-analysis of 5 randomized, controlled trials supports the use of clonazepam in the treatment of acute bipolar mania [Curtin 2004]. Additional trials may be necessary to further define the role of clonazepam in this condition.

APA guidelines for the treatment of patients with bipolar disorder suggest that the use of benzodiazepines, such as clonazepam, in sedative doses may be useful short-term as adjunctive therapy when used with traditional mood-stabilizing agents. CANMAT guidelines for the management of patients with bipolar disorder recommend against the use of benzodiazepines as monotherapy, but suggest they may be useful adjunctive therapy for the sedation of acutely agitated patients. Similarly, WFSBP guidelines for the treatment of acute mania in bipolar disorder recommend benzodiazepines as adjunctive therapy to target anxiety and insomnia in patients taking mood-stabilizing agents.

Burning mouth syndrome

Data from a prospective open-label study in patients with mouth burning without oral mucosal lesions suggest that clonazepam may be helpful in patients with this condition [Grushka 1998]. Additional data from a double-blind, randomized, multicenter, parallel group study using topical (buccal administration) clonazepam demonstrated improvement in pain intensity [Gremeau-Richard 2004]. In a systematic review, clonazepam is a therapeutic option in the treatment of this condition; however, use should be limited due to the risk of benzodiazepine dependence [Buchanan 2008]. Additional trials are necessary to further define the role of clonazepam for the treatment of this condition.

Essential tremor

Data from a limited number of patients studied (case series) suggest that clonazepam may be beneficial in reducing the frequency of essential tremor [Biary 1987]. On the contrary, data from a small randomized, double-blind, placebo-controlled trial demonstrated that clonazepam was not an effective treatment [Thompson 1984]. Additional data may be necessary to further define the role of clonazepam in this condition.

Rapid eye movement (REM) sleep behavior disorder

Based on the American Academy of Sleep Medicine (AASM) Best Practice Guide for the Treatment of REM Sleep Behavior Disorder (RBD), clonazepam is an effective and recommended treatment option for patients with this condition; however, it should be used with caution in patients with dementia, gait disorders, or concomitant obstructive sleep apnea [AASM [Aurora 2010]].

Restless legs syndrome

Data from a limited number of patients in small controlled trials suggest that clonazepam may be beneficial for the treatment of periodic limb movements and poor sleep associated with restless legs syndrome [Montagna 1984], [Peled 1987], [Saletu 2001], [Schenck 1996]. Additional data may be necessary to further define the role of clonazepam in this condition.

Based on the updated American Academy of Sleep Medicine guidelines, there are insufficient data available to recommend benzodiazepines, specifically clonazepam, for first-line treatment of RLS. Based on the EFNS/ENS/ESRS joint task force guidelines on the management of restless legs syndrome, clonazepam is probably effective for the treatment of primary RLS; however, this recommendation was based on only one open-label trial. The American Academy of Neurology (AAN) guidelines state that there is insufficient evidence to support or refute the use of clonazepam in the treatment of RLS.

Tardive dyskinesia

Data from a limited number of patients in a double-blind, randomized, placebo-controlled crossover trial suggests that clonazepam may be beneficial for the treatment of tardive dyskinesia [Thaker 1990]. Additional data may be necessary to further define the role of clonazepam in this condition.

Tic disorders

Data from a limited number of patients studied in a single-blind and two retrospective studies suggest that clonazepam may be beneficial for multifocal tic disorder or Tourette disorder. Additional data may be necessary to further define the role of clonazepam in these conditions.

Contraindications

Hypersensitivity to clonazepam, other benzodiazepines, or any component of the formulation; significant liver disease; acute narrow-angle glaucoma

Topical: May administer topically with 1 mg 3 times daily (after each meal). Note: Patient should be instructed to suck on the tablet, retain saliva in mouth near the pain sites without swallowing for 3 minutes, and then expectorate saliva (Gremeau-Richard 2004).

Restless leg syndrome (off-label use): Oral: Initial: 1 mg 30 minutes prior to bedtime; increase dose by 0.5 to 1 mg at weekly intervals. Doses up to 2 mg once daily have been used in clinical trials (Montagna 1984; Peled 1987; Saletu 2001). Additional data may be necessary to further define the role of clonazepam in the treatment of this condition.

Tardive dyskinesia (off-label use): Oral: Initial: 1 mg/day; adjust dosage based on response and tolerability by 1 mg/day every 3 to 4 days up to a maximum dose of 4.5 mg/day (Thaker 1990).

Dosing: Geriatric

Refer to adult dosing. Initiate with low doses and observe closely.

Dosing: Pediatric

Seizure disorders: Oral:

Infants, Children ≤10 years or ≤30 kg:

Initial daily dose: 0.01 to 0.03 mg/kg/day (maximum initial dose: 0.05 mg/kg/day) given in 2 to 3 divided doses; increase by no more than 0.25 to 0.5 mg every third day until seizures are controlled or adverse effects seen.

Usual maintenance dose: 0.1 to 0.2 mg/kg/day divided 3 times daily.

Children >10 years or >30 kg and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Clonazepam metabolites may accumulate in patients with renal impairment.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution. Clonazepam undergoes hepatic metabolism. Contraindicated in patients with significant hepatic impairment.

Extemporaneously Prepared

A 0.1 mg/mL oral suspension may be made with tablets and one of three different vehicles (cherry syrup; a 1:1 mixture of Ora-Sweet® and Ora-Plus®; or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®). Crush six 2 mg tablets in a mortar and reduce to a fine powder. Add 10 mL of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “protect from light”. Stable for 60 days when stored in amber prescription bottles in the dark at room temperature or refrigerated.

Administration

To reduce somnolence, administration of one dose at bedtime may be desirable.

Orally-disintegrating tablet: Open pouch and peel back foil on the blister; do not push tablet through foil. Use dry hands to remove tablet and place in mouth. May be swallowed with or without water. Use immediately after removing from package.

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Phenytoin: May decrease the serum concentration of ClonazePAM. Clonazepam may also alter concentrations of Phenytoin. Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

ALERT: U.S. Boxed Warning

Risk from concomitant use with opioids:

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

Warnings/Precautions

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving); increased risk may occur with the use of multiple anticonvulsants.

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving; cooking and eating food, and making phone calls while asleep have also been noted with benzodiazepines (Dolder 2008).

• Depression: Use caution in patients with depression, particularly if suicidal risk may be present.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• Glaucoma: May be used in patients with open angle glaucoma who are receiving appropriate therapy; contraindicated in acute narrow angle glaucoma.

• Hepatic impairment: Use with caution in patients with hepatic impairment; accumulation likely to occur. Contraindicated in patients with significant hepatic impairment.

• Porphyria: Use with caution in patients with porphyria; may have a porphyrogenic effect.

• Renal impairment: Use with caution in patients with renal impairment; clonazepam metabolites are renally eliminated.

• Respiratory disease: Clonazepam may cause respiratory depression and may produce an increase in salivation; use with caution in patients with compromised respiratory function (eg, chronic obstructive pulmonary disease, sleep apnea) and in patients who have difficulty handling secretions.

Concurrent drug therapy issues:

• Concomitant use with opioids: [US Boxed Warning]: Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.

Other warnings/precautions:

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Worsening of seizures may occur when added to patients with multiple seizure types. Loss of anticonvulsant activity may occur (typically within 3 months of initiation); dose adjustment may be necessary. Periodically reevaluate the long-term usefulness of clonazepam for the individual patient.

• Tolerance: Clonazepam is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the anticonvulsant effects. It does not develop to the anxiolytic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

• Withdrawal: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy (Brogden 1988).

Monitoring Parameters

Pregnancy Considerations

Clonazepam crosses the placenta. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) has been reported with some benzodiazepines, including clonazepam (Bergman 1992; Iqbal 2002; Wikner 2007). A combination of factors influences the potential teratogenicity of anticonvulsant therapy. When treating pregnant females with epilepsy, monotherapy with the lowest effective dose and avoidance medications known to have a high incidence of teratogenic effects is recommended (Harden 2009; Wlodarczyk 2012). When treating pregnant females with panic disorder, psychosocial interventions should be considered prior to pharmacotherapy (APA 2009).

Patients exposed to clonazepam during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.